The National Institute of Neurological Disorders and Stroke (NINDS) and the Office of Rare Disorders (ORD) invite grant applications
for central nervous system (CNS) therapy development for lysosomal storage disorders.*

Lysosomal storage disorders include about 50 metabolic diseases that collectively affect approximately 1 in 5000 live births.
Each of these diseases has heterogeneous pathophysiology and clinical manifestations resulting from deficient activity of
specific hydrolases. In some cases, the genetic defect can be in an activator protein for a lysosomal hydrolase or a transporter
protein for the metabolites. All of these deficiencies lead to a characteristic pathological accumulation and storage of the
substrate for that enzyme in the lysosomes. The consequent accumulation of undigested metabolites in lysosomes leads to multi-systemic
dysfunction, including progressive neurologic deterioration, mental retardation, organomegaly, blindness, and early death.

Examples of research topics include, but are not limited to: novel delivery methods for drugs, cells, enzymes, and genes across
around the blood-brain barrier (BBB); new types of therapy, including substrate reduction therapy; RNAi-mediated therapy of
downstream targets; identification of therapeutic windows of opportunity by characterizing pathophysiological processes; use
of non-invasive measures of organ function to identify, characterize, and validate diagnostic biomarkers, intermediate surrogate
endpoints, and prognostic biomarkers; estimation of the magnitude of treatment effects based on validated biomarkers that
reflect underlying pathogenesis; and development and validation of clinical tools, such as a rating scale or predictor of
clinical outcome.